Opiates, and in particular, morphine, are routinely administered for the treatment of moderate to severe pain. Agents that are less potent than morphine, such as codeine, mixed agonist-antagonist opioids, and non-opiate analgesics, including non-steroidal anti-inflammatory drugs (NSAIDS) are often used to relieve mild to moderate pain. Because of the well-known side effects of opiates, including chemical dependence and respiratory depression, there is a strong need for a non-opiate based analgesic for moderate to severe pain that would equal or exceed the potency of opiate analgesics, yet lack the serious side effects associated with the administration of opiates. Spande, et al., reported in 1992 that a potent nonopiate analgesic had been isolated from the skins of the Ecuadoran poison frog, Epipedobates tricolor. Spande, et al., 1992 J. Am. Chem. Soc., 114, 3475-3478. The structure of the compound was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance as exo-2-(2-chloro-5-pyridyl)-7-azabicyclo[2.2.1]heptane (see FIG. 1). The compound, which was named epibatidine, is the first member of the class of 7-azabicyclo[2.2.1]heptane compounds to be found in nature. Limited pharmacological evaluation of epibatidine indicated that it is approximately 500 times more potent than morphine in eliciting the Straub-tail response, and that this effect is not reversed by the opiate antagonist naloxone. In the hot plate analgesia assay, epibatidine is approximately 200 times as potent as morphine. It has also been determined that epibatidine has a negligible affinity for opiate receptors (1/8000 times that of morphine). Based on this data, it appears that epibatidine is a very potent analgesic that acts via a non-opiate mechanism. Since epibatidine was isolated from the skins of the Ecuadoran poison frog, its identification and characterization was not based on the synthesis of the compound. In fact, compounds in the family of 7-azabicyclo[2.2.1]-heptanes and -heptenes (also referred to as 7-azanorbornanes and 7-azanorbornenes, respectively) have historically been difficult to synthesize.
A possible entry into the 7-azabicyclo[2.2.1]-heptane and -heptene ring systems involves the construction of the bicyclic ring through the 2+4 cycloaddition of appropriately substituted 3-vinyl pyridine and pyrrole fragments, as indicated below. ##STR1## Unfortunately, pyrrole and its derivatives readily undergo substitution reactions upon treatment with dienophiles (Diels, O. and Alder, K., Ann. 1932 498, 1.), with only a few exceptions reported (Wittig, G., Angew Chem. 1957 69, 245). The partial aromatic character of pyrrole limits its reactivity as a diene and Michael-type addition products usually dominate. (Jones, R. A., The Chemistry of Heterocyclic Compounds, v.48 Pyrroles Wiley & Sons: New York. 1990.) Rate and yield enhancement of the Diels-Alder reaction between pyrroles and olefins have been obtained using Lewis acids (Donnini, G. P.; Just, G. J. Heterocycl. Chem. 1977, 14, 1423; Bansal, R. C.; McCulloch, A. W.; McInnes, A. G. Can. J. Chem. 1969, 47, 2391), and high pressures (Kotsuki, H.; Mori, Y; Nishizawa, H.; Masamitsu, O.; Matsuoka, K. Heterocycles, 1982, 19, 1915; Drew, M. G. B.; George, A. V.; Isaacs, is N. S.; Rzepa, H. S. T. C. S. Perkin Trans 1, 1985, 1277), but thus far these approaches have been limited in scope. The limitation in these reactions can often be traced to the inherent instability of the 7-azabicyclo[2-2.1]hept-2-ene products with respect to either retro-cycloaddition or retro-Mannich and re-aromatization pathways. This is especially true for cases where the resulting olefin is functionalized by electron-withdrawing groups. (Altenbach, H. J.; constant, D.; Martin, H. D.; Mayer, B.; Muller, M.; Vogel, E. Chem. Ber. 1991, 124, 791.) An alternative method for the synthesis of the 7-azanorbornane system was reported by Fraser, et al. (Can. J. Chem. 1970, 48, 2065) but the long synthetic route and drastic reaction conditions involved are unsuitable for the synthesis of epibatidine. For a review of 7-azanorbornene chemistry see: Kricka, L. J.; Vernon, J. M. Adv. in Heterocycl. Chem. 1974, 16, 87.
N-Carboalkoxypyrrole has been used in Diels-Alder reactions with several acetylenic dienophiles to prepare norbornane derivatives. None of these reported schemes, however, place an aromatic or heteroaromatic group in the important is 2-position of the heptane or heptene ring. (Altenbach, H-J., et al., Chem. Ber. 1991, 124, 791; Altenbach, H-J., et al., Angew. Chem. Int. Ed. Engl. 1992 21(10), 778; Gabel, N. W., J. Org. Chem. 1962, 27, 301; Toube, T. P. (1992) in: Pyrroles, Part 2 (Jones, R. A., ed.) John Wiley, New York. pp 92-95.)
In light of the analgesic potency of epibatidine as well as the strong need for new potent, non-opiate analgesics, it would be useful to provide methods for the synthesis of 7-azabicyclo[2.2.1]-heptane and -heptene derivatives that have pharmacological activity, and in particular, analgesic activity, or that can be derivatized to compounds with pharmacological activity.
Therefore, it is an object of the present invention to provide new 7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic activity.
It is another object of the present invention to provide methods for the synthesis of 7-azabicyclo[2.2.1]-heptane and -heptene derivatives with analgesic activity.
It is still another object of the present invention to provide new methods for the treatment of pain.